RESUMO
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, â¼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
Assuntos
Anormalidades Craniofaciais/genética , Nanismo/genética , Heterogeneidade Genética , Deformidades Congênitas dos Membros/genética , Anormalidades Urogenitais/genética , Via de Sinalização Wnt/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Segregação de Cromossomos/genética , Anormalidades Craniofaciais/diagnóstico , Diagnóstico Diferencial , Nanismo/diagnóstico , Feminino , Genes Dominantes , Estudos de Associação Genética , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Fenótipo , Anormalidades Urogenitais/diagnósticoRESUMO
Purpose. We present a case with Klippel-Trenaunay (KT) syndrome that had unilateral mature cataract and vitreoretinopathy. Case Report. A 17-year-old boy with KT syndrome presented to the clinic of ophthalmology for low vision in the right eye. His best corrected visual acuity (BCVA) was hand motion in the right eye and 20/20 in the left eye. Anterior segment examination revealed mature cataract in the right. During the physical examination, port-wine stains were noted over right side of his face, ankle, and toes. He had asymmetric face and his head was larger on the right side. Leg lengths were symmetrical, although he had skin hypertrophy. Cranial magnetic resonance imaging studies showed cortical atrophy discordant to his age, asymmetric vascular dilatations in the right hemisphere, hypertrophy in the right periorbital soft tissue, and choroidal plexus. The patient received an uncomplicated cataract surgery. His BCVA in the right eye improved to 20/200 after the surgery. After removing cataractous lens, we were able to examine the fundus that revealed severe vitreoretinopathy and choroidal hemangioma. Conclusion. This case emphasizes the importance of prompt ophthalmic examination in patients with KT syndrome.